ITMI940717A1 - PHARMACEUTICAL COMPOSITIONS WITH ANTI-TOXIC ACTIVITY - Google Patents
PHARMACEUTICAL COMPOSITIONS WITH ANTI-TOXIC ACTIVITY Download PDFInfo
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- ITMI940717A1 ITMI940717A1 IT000717A ITMI940717A ITMI940717A1 IT MI940717 A1 ITMI940717 A1 IT MI940717A1 IT 000717 A IT000717 A IT 000717A IT MI940717 A ITMI940717 A IT MI940717A IT MI940717 A1 ITMI940717 A1 IT MI940717A1
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- IT
- Italy
- Prior art keywords
- glutathione
- pharmaceutical compositions
- transferase
- compositions according
- glutathicne
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 12
- 230000001147 anti-toxic effect Effects 0.000 title claims description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 31
- 108010024636 Glutathione Proteins 0.000 claims description 19
- 102000005720 Glutathione transferase Human genes 0.000 claims description 13
- 108010070675 Glutathione transferase Proteins 0.000 claims description 13
- 229960003180 glutathione Drugs 0.000 claims description 12
- 102000004357 Transferases Human genes 0.000 claims description 7
- 108090000992 Transferases Proteins 0.000 claims description 7
- 238000001990 intravenous administration Methods 0.000 claims description 6
- 238000007918 intramuscular administration Methods 0.000 claims description 5
- 210000002826 placenta Anatomy 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 208000019423 liver disease Diseases 0.000 claims description 3
- 230000021615 conjugation Effects 0.000 claims description 2
- 230000004090 etiopathogenesis Effects 0.000 claims description 2
- 230000002489 hematologic effect Effects 0.000 claims description 2
- 230000002440 hepatic effect Effects 0.000 claims description 2
- 239000007922 nasal spray Substances 0.000 claims description 2
- 229940097496 nasal spray Drugs 0.000 claims description 2
- 230000000926 neurological effect Effects 0.000 claims description 2
- 239000002676 xenobiotic agent Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 108010044467 Isoenzymes Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000002634 anti-blastic effect Effects 0.000 description 1
- 238000011138 biotechnological process Methods 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000000624 ear auricle Anatomy 0.000 description 1
- 239000006167 equilibration buffer Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 230000007866 hepatic necrosis Effects 0.000 description 1
- 206010019692 hepatic necrosis Diseases 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Descrizione dell'invenzione industriale avente per titolo: COMPOSIZIONI FARMACEUTICHE AD ATTIVITA ANTITOSSICA" Description of the industrial invention entitled: PHARMACEUTICAL COMPOSITIONS WITH ANTI-TOXIC ACTIVITY "
L'oggetto della presente invenzione è costituito da conposizioni farmaceutiche ad attività antitossica, caratterizzate dal fatto che in qualità di principio attivo contengono un'associazione di glutaticne ridotto e di giutatione trasferasi. The object of the present invention consists of pharmaceutical compositions with antitoxic activity, characterized in that as an active principle they contain an association of reduced glutathione and jutathione transferase.
Il glutatione è un fattore inportante nel metabolismo di molte sostanze tossiche sia endogene che esogene. La alchilazione da parte del glutatione di metaboliti o composti esogeni elettrofili, e la riduzione di specie chimiche ossidanti altamente reattive, sono due delle funzioni esercitate dal glutatione nella protezione della cellula o dei tessuti. E' noto l'uso in terapia di preparati a base di glutaticne che agiscono fornendo all'organismo la possibilità di ripristino dei livelli di glutaticne scesi per effetto delle sostanze tossiche al di sotto dei livelli-soglia. In particolare si può prospettare un uso del glutatione ridotto in numerose forme patologiche o’in varie situazioni a rischio: epatopatie croniche di varia eziologia; Glutathione is an important factor in the metabolism of many toxic substances, both endogenous and exogenous. The alkylation by glutathione of metabolites or electrophilic exogenous compounds, and the reduction of highly reactive oxidizing chemical species, are two of the functions exerted by glutathione in protecting the cell or tissues. The use in therapy of glutathicne preparations is known, which act by providing the body with the possibility of restoring the levels of glutathicne which have fallen due to the effect of toxic substances below the threshold levels. In particular, a reduced use of glutathione can be envisaged in numerous pathological forms or in various risk situations: chronic liver diseases of various etiologies;
prevenzione e terapia di danni a livello cerebrale, epatico, renale o sistemico determinati da vari tipi di farmaci; prevention and therapy of brain, liver, kidney or systemic damage caused by various types of drugs;
- prevenzione e terapia di danni ed effetti collaterali a seguito di terapia antiblastica o di terapia radiante. - prevention and therapy of damage and side effects following antiblastic therapy or radiation therapy.
Tuttavia l'efficacia dei detti preparati è in molti casi insoddisfacente. Si è ora sorprendentemente trovato che un'associazione di giutaticne ridotto e di glutaticne trasferasi (in particolare glutaticne trasferasi acida) esercita un’azione protettiva sinergica, tale da rendere le composizioni farmaceutiche secondo l'invenzione sensibilmente più efficaci rispetto a quelle note. However, the effectiveness of said preparations is in many cases unsatisfactory. It has now surprisingly been found that an association of reduced jutathic and glutathic acid transferase (in particular glutathic acid transferase) exerts a synergistic protective action, such as to make the pharmaceutical compositions according to the invention significantly more effective than the known ones.
La cosiddetta "glutatione trasferasi" è rappresentata in realtà da una famiglia di isoenzimi con caratteristiche chimico-fisiche diverse. Seno infatti presenti quattro classi di isoenzimi: alfa, mu, Pi e Teta, che presentano, pur deputate tutte alle reazioni di detossifreazione, caratteristiche molecolari e funzionali diverse tra di loro. In particolare l'isoenzima Pi, con punto isoelettrico acido, è la forma presente nella maggior parte dei tessuti umani ed anche in quelli fetali, tuttavia in concentrazioni plasmatiche molto basse (circa 1-2 ng/ml). Essa è isolabile da placenta umana seguendo uno schema classico di purificazione descritto in letteratura. The so-called "glutathione transferase" is actually represented by a family of isoenzymes with different chemical-physical characteristics. In fact, there are four classes of isoenzymes: alpha, mu, Pi and Theta, which, although all of them are involved in detoxification reactions, have different molecular and functional characteristics. In particular, the isoenzyme Pi, with an acid isoelectric point, is the form present in most human tissues and also in fetal ones, however in very low plasma concentrations (about 1-2 ng / ml). It can be isolated from human placenta following a classical purification scheme described in the literature.
Una placenta a termine, lavata con soluzione fisiologica, ed eventualmente conservata a -20°C anche per molti mesi, viene omogenata in tampone fosfato di potassio pH 6,5 contenente glutatione ridotto (Sigma, St.Louis, USA) 1 mM ed EDTA anch'esso 1 mM. L'omogenato viene centrifugato a 10.000 x g per 30 minuti ed il super atante conservato. Si procede ad un lavaggio del precipitato con lo stesso tampone e dopo ulteriore centrifugazione i due super atanti seno uniti e dializzati contro lo stesso tampone fosfato privo di glutatione. A term placenta, washed with physiological solution, and possibly stored at -20 ° C even for many months, is homogenized in potassium phosphate buffer pH 6.5 containing reduced glutathione (Sigma, St. Louis, USA) 1 mM and EDTA also 1 mM. The homogenate is centrifuged at 10,000 x g for 30 minutes and the super atant is preserved. The precipitate is washed with the same buffer and after further centrifugation the two superatants are united and dialyzed against the same glutathione-free phosphate buffer.
L'omogenato chiarificato (circa 1500 mi) viene passato attraverso una colonna di affinità di epossi-sefarosio attivato con glutatione (dimensioni di 2,5 x 8 cm) ed equilibrata con lo stesso tampone di dialisi. Dopo lavaggio della colonna con il tampone di equilibratura la glutatione trasferasi legata viene eluita con tampone TRIS-HCl 10 nM pH 9,2 contenente glutatione 5 nM. Concentrata per ultrafiltrazione e dializzata la glutatione trasferasi così ottenuta è omogenea in elettroforesi su gel di poliacrilamide e presenta tutte le caratteristiche catalitiche e chimico-fisiche descritte in letteratura. The clarified homogenate (approximately 1500 mL) is passed through a glutathione-activated epoxy-sepharose affinity column (size 2.5 x 8 cm) and equilibrated with the same dialysis buffer. After washing the column with the equilibration buffer, the bound glutathione transferase is eluted with 10 nM pH 9.2 TRIS-HCl buffer containing 5 nM glutathione. Concentrated by ultrafiltration and dialyzed, the glutathione transferase thus obtained is homogeneous in polyacrylamide gel electrophoresis and has all the catalytic and physico-chemical characteristics described in the literature.
La rasa media della preparazione è di circa 10-15 mg di enzima per kg di placenta umana. The average rasa of the preparation is about 10-15 mg of enzyme per kg of human placenta.
Per lo studio dell'effetto protettivo è stato scelto un modello di intossicazione acuta da brcmobenzene, che è noto causare necrosi epatica,e cane marker del danno epatico sono stati misurati i livelli plasmatici di AST (aspartato aminotrasferasi) e di ALT {alanina aminotrasferasi). A model of acute brchmobenzene intoxication, which is known to cause hepatic necrosis, was chosen for the study of the protective effect, and plasma levels of AST (aspartate aminotransferase) and ALT (alanine aminotransferase) were measured. .
Conigli albini, dopo alimentazione ad libitum per una settimana, sono stati mantenuti a digiuno durante la notte e quindi utilizzati per la sperimentazione. Il bromobenzene è stato preparato miscelandolo con tre volumi di olio d'oliva e quindi è stato sonninistrato per via orale ad una concentrazione di 10 mmoli per kg di peso corporeo. Il glutatione ridotto e la glutatione trasferasi seno stati preparati in forma liofila e ripresi con acqua bidistillata apirogena in soluzione contenente, rispettivamente, 10 mg di glutatione ridotto e 10 mg di glutatione ridotto più 10 microgrammi di glutatione trasferasi da placenta umana. Albino rabbits, after ad libitum feeding for one week, were fasted overnight and then used for experimentation. Bromobenzene was prepared by mixing it with three volumes of olive oil and then administered orally at a concentration of 10 mmol per kg of body weight. The reduced glutathione and glutathione transferase were prepared in lyophilic form and taken up with apyrogenic double distilled water in a solution containing, respectively, 10 mg of reduced glutathione and 10 mg of reduced glutathione plus 10 micrograms of glutathione transferase from human placenta.
Tre gruppi di 6 conigli ciascuno sono stati trattati nel modo seguente: Three groups of 6 rabbits each were treated as follows:
1° gruppo: trattato con solo bromobenzene; 1st group: treated with bromobenzene only;
2° gruppo: trattato con bromobenzene e con iniezione di glutatione al tempo zero e dopo sei ore; 2nd group: treated with bromobenzene and with glutathione injection at time zero and after six hours;
3° gruppo: trattato con bromobenzene e con iniezione di glutatione e glutatione trasferasi al tempo zero e dopo sei ore; 3rd group: treated with bromobenzene and with injection of glutathione and glutathione transferase at time zero and after six hours;
Al tenpo zero e dopo 3 ore, 6 ore, 9 ore e 12 ore sono stati eseguiti prelievi di sangue periferico dalla vena del lobo dell’orecchio. La stessa vena è stata utilizzata per la somministrazione del glutatione e del glutatione addizionato di glutatione trasferasi. Il sangue prelevato dopo opportuno sieraggio è stato utilizzato per la determinazione delle attività delle transaminasi con una metodica U.V.NADH dipendente. At zero time and after 3 hours, 6 hours, 9 hours and 12 hours, peripheral blood samples were taken from the earlobe vein. The same vein was used for the administration of glutathione and glutathione added with glutathione transferase. The blood taken after an appropriate serum was used for the determination of the transaminase activities with a U.V.NADH dependent method.
Nella tabella sono riportati i valori ottenuti,espressi cane UI/1. Da questi risultati risulta evidente cane esista una azione protettiva sinergica esercitata dall'associazione glutatione ridotto- glutaticne trasferasi. The table shows the values obtained, expressed as IU / 1. From these results it is evident that there is a synergistic protective action exerted by the reduced glutathione-glutaticne transferase association.
L'associazione sopra descritta è quindi suscettibile di inpiego per una migliore protezione dell'organismo sia in epatopatie di varia eziopatogenesi,che per possibili danni renali, epatici, neurologici ed ematologiei determinati da livelli anche bassi di vari xenobiotici, ed inoltre in qualsiasi situazione fisiopatologica nella quale sia richiesta una protezione esercìtabile mediante reazioni di coniugazione al glutatione. The association described above is therefore susceptible of use for a better protection of the organism both in hepatopathies of various etiopathogenesis, and for possible renal, hepatic, neurological and haematological damage caused by even low levels of various xenobiotics, and also in any pathophysiological situation. in which protection is required which can be exercised through conjugation reactions to glutathione.
Quantunque l'invenzione sia stata esemplificata ccn specifico riferimento all'impiego di glutatione trasferasi Pi, è chiaro che essa può venire attuata anche impiegando altre glutatione trasferasi (e loro miscele), ottenute siaper estrazione sia con procedimenti biotecnologici. Although the invention has been exemplified with specific reference to the use of glutathione transferase Pi, it is clear that it can also be carried out using other glutathione transferases (and their mixtures), obtained both by extraction and by biotechnological processes.
L’associazione glutatione ridotto-glutatione trasferasi può essere utilizzata in conposizioni farmaceutiche per somministrazicne intramuscolare, endovenosa e per aerosol. The reduced glutathione-glutathione transferase association can be used in pharmaceutical compositions for intramuscular, intravenous and aerosol administration.
Nella somministrazione endovenosa il preparato può essere aggiunto a soluzioni perfusionali quelli gluoosale, fisiologiche, elettrolitiche. In intravenous administration, the preparation can be added to perfusional solutions, those gluoosal, physiological, electrolytic.
Si riportano a titolo illustrativo alcuni esempi di formulazioni farmaceutiche secondo l ' invenzione . Some examples of pharmaceutical formulations according to the invention are reported by way of illustration.
Le quantità in peso dei conponenti attivi nelle varie fonte oscillano fra i 100 e i 600 mg per il glutaticne ridotto e fra i 10 e i 100 mcg per la glutatione transferasi. The quantities by weight of the active components in the various sources range between 100 and 600 mg for reduced glutathione and between 10 and 100 mcg for glutathione transferase.
Esempio 1 Example 1
Fiale per uso intramuscolare o endovenoso. Ampoules for intramuscular or intravenous use.
Ogni fiala liofilizzata contiene: Each lyophilized vial contains:
Esempio 2 Example 2
Fiale per uso intramuscolare o endovenoso. Ampoules for intramuscular or intravenous use.
Ogni fiala liofilizzata contiene: Each lyophilized vial contains:
Esempio 3 Example 3
Fiale per uso intramuscolare o endovenoso. Ampoules for intramuscular or intravenous use.
Ogni fiala liofilizzata contiene: Each lyophilized vial contains:
Esempio 4 Example 4
Spray nasale. Nasal spray.
1 mi di soluzione contiene: 1 ml of solution contains:
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI940717A IT1269316B (en) | 1994-04-15 | 1994-04-15 | PHARMACEUTICAL COMPOSITIONS WITH ANTI-TOXIC ACTIVITY |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI940717A IT1269316B (en) | 1994-04-15 | 1994-04-15 | PHARMACEUTICAL COMPOSITIONS WITH ANTI-TOXIC ACTIVITY |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| ITMI940717A0 ITMI940717A0 (en) | 1994-04-15 |
| ITMI940717A1 true ITMI940717A1 (en) | 1995-10-15 |
| IT1269316B IT1269316B (en) | 1997-03-26 |
Family
ID=11368599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ITMI940717A IT1269316B (en) | 1994-04-15 | 1994-04-15 | PHARMACEUTICAL COMPOSITIONS WITH ANTI-TOXIC ACTIVITY |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1269316B (en) |
-
1994
- 1994-04-15 IT ITMI940717A patent/IT1269316B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| IT1269316B (en) | 1997-03-26 |
| ITMI940717A0 (en) | 1994-04-15 |
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